Developmental reprogramming of cancer susceptibility

Abstract

Gene-environment interactions have been traditionally understood to promote the acquisition of mutations that drive multistage carcinogenesis, and, in the case of inherited defects in tumour suppressor genes, additional mutations are required for cancer development. However, the developmental origins of health and disease (DOHAD) hypothesis provides an alternative model whereby environmental exposures during development increase susceptibility to cancer in adulthood, not by inducing genetic mutations, but by reprogramming the epigenome. We hypothesize that this epigenetic reprogramming functions as a new type of gene-environment interaction by which environmental exposures target the epigenome to increase cancer susceptibility.

Figure 1. The thrifty phenotype hypothesis

Plasticity of the epigenome during development affords an opportunity for the developing organism to ‘pre-adapt’ to the future adult environment, which provides a survival advantage. However, in settings in which the fetal environment does not match the adult environment — for example, fetal development in a nutrient-poor environment (such as maternal starvation) coupled with a nutrient-rich adult environment — the resulting ‘catch-up’ growth and disconnection between fetal programming and the adult environment can predispose to adult metabolic disease, including obesity and type II diabetes.

Figure 2. Developmental reprogramming dormancy

Programming of the epigenome primarily occurs during development, although some epigenetic programmes are executed in response to later-life cues such as puberty. As a result, epigenetic reprogramming by environmental oestrogens may remain dormant until after these cues later in life, such as until after puberty. In the reproductive tract of intact animals that are perinatally exposed to environmental oestrogens, lactotransferrin (Ltf) and high-mobility group nucleosome-binding domain 5 (Hmgn5) become hypomethylated, which increases their expression in adult animals. However, in the absence of hormone (that is, castration), in adult animals that are neonatally exposed to environmental oestrogens, these target genes remain hypermethylated, which decreases their expression.

Figure 3. Model of the engagement of the epigenetic machinery by environmental oestrogens via non-genomic ER signalling

Environmental oestrogens can activate non-genomic oestrogen receptor (ER) signalling pathways in cells during developmental reprogramming. These signalling cascades target epigenetic ‘readers’, ‘writers’ and ‘erasers’ for phosphorylation (P) (and perhaps other post-translational modifications), modulating their activity and disrupting epigenetic programming. In the case of the histone methyltransferase (HMT) enhancer of zeste homologue 2 (EZH2), phosphory-lation by AKT inhibits its ability to methylate histone H3, which reduces the levels of repressive tri-methylation of H3K27 in the developing uterus. This developmental reprogramming results in elevated expression of oestrogen-responsive genes in the adult uterus, promoting tumorigenesis. Although we know little about how post-translational modifications might affect the activity of other readers, writers and erasers, it is possible that non-genomic signalling could also increase their activity. Depending on whether the effect is on a repressive or an activating methyl mark, the resulting reprogramming could decrease or increase gene expression in the adult tissue

Figure 4. Developmental reprogramming of the penetrance of defects in tumour suppressor genes

Developmental exposure to xenoestrogens disrupts the epigenetic machinery in the cell. a | In animals carrying a defect in the tuberous sclerosis 2 (Tsc2) tumour suppressor gene, this ‘oestrogenized’ phenotype in the adult uterus promotes tumour development in genetically susceptible animals, which increases the penetrance of the Tsc2 defect from 65% to 100%. b | This reprogramming may act via alterations in both histone and DNA methylation. For example, diethylstilbestrol (DES) exposure inhibits enhancer of zeste homologue 2 (EZH2) and decreases the levels of repressive trimethylation of H3K27. As a result, hormone-responsive genes in the uterus become hyper-responsive to hormone, exhibiting significantly elevated expression to even low levels of steroid hormones, which again increases the penetrance of tumour susceptibility.